Bird flu inflammation

Scientists might have identified one of the reasons why the bird flu virus H5N1 is so deadly to humans. A study published last November in the open access journal Respiratory Research reveals that, in human cells, the virus can trigger levels of inflammatory proteins more than 10 times higher than the common human flu virus H1N1. This might contribute to the unusual severity of the disease caused by H5N1 in humans, which can escalate into life-threatening pneumonia and acute respiratory distress.

Michael Chan and colleagues from the University of Hong Kong and collaborators in Vietnam, studied the levels of a subset of the pro-inflammatory proteins called ‘cytokines’ and ‘chemokines’, induced by the virus H5N1 in human lung cells, in vitro. The authors compared protein levels induced by strains of the H5N1 virus that had appeared in Hong Kong in 1997 (H5N1/97) and Vietnam in 2004 (H5N1/04), with levels induced by the human flu virus H1N1.

Their results show that H5N1 is a much more potent inducer of proinflammatory proteins than H1N1. Twenty-four hours after infection with H5N1/04, the levels of the chemokine IP-10 in bronchial epithelial cells reach 2200 pg/ml, whereas in cells infected with H1N1 they only reach 200pg/ml. In H5N1/97-infected cells, IP-10 levels reach 1750 pg/ml.

Similar results were found for other chemokines and cytokines. Chemokines and cytokines are the “messengers of the immune system” and are critical in co-ordinating and regulating the immune response. Altering this balance is likely to lead to an uncontrolled inflammatory response in the lung and probably explains, at least in part, the severe lung inflammation associated with avian flu virus H5N1.



Anti-clotting tech

Volunteers at the Jack and Linda Gill Heart Institute at the University of Kentucky (UK) were the first ever to receive a new anti-clotting therapy. The drug and its antidote are being developed for their effectiveness in preventing blood clots while at the same time providing physicians the ability to rapidly reverse the effects of the blood thinner to help safeguard patients against uncontrolled bleeding.

More than 12 million patients are prescribed socalled "blood thinners" each year to prevent the formation of clots, which can block blood vessels, causing heart attacks, strokes and other debilitating or lifethreatening conditions. Blood thinners, or antithrombotics, pose a risk of bleeding, particularly during surgery. The ability to stop the anti-clotting effects quickly could help protect patients from uncontrolled bleeding.

The Gill Heart Institute is one of two sites participating in the Phase 1 trial and is the first site to use the anti-clotting drug and its antidote. This clinical trial will examine the drug's safety and tolerability in healthy volunteers as well as the antidote's ability to quickly reverse its effects. Although other new antithrombotics are undergoing testing in the Untied States, this drug is believed to be the first of its kind.

“This class of drugs is a very promising technology that allows for the development of 'designer' drugs and their antidotes simultaneously,” said Dr Steven R Steinhubl, the study's principal investigator at UK and director of cardiovascular education and clinical research at the Gill Heart Institute and a UK College of Medicine associate professor of cardiology. “It could have far-reaching implications.”



H5N1 test

A diagnostic test that detects all the major human respiratory viruses, including H5N1 (Avian Flu) and SARS Corona, has been developed by a virologist at McMaster University, and is about to undergo clinical evaluation.

Jim Mahony and his lab at McMaster University collaborated with Tm Bioscience Corporation, a Torontobased company that conducts genetic testing, says the test reduces the laborious and long process involved in acquiring definitive results. “This test could play a major role during an outbreak or epidemic by clearly identifying infected individuals early in the outbreak and limiting the spread of virus in the community,” said Mahony, director of the McMaster University Regional Virology and Chlamydiology Laboratory at St Joseph's healthcare, and president of the Pan American Society for Clinical Virology.

“It will assist public health authorities in determining which specific virus, if any, is present in a patient who is presenting flu symptoms.” Mahony's lab provided the genetic sequences for the probes and primers to build the test and assisted in establishing key test parameters for the detection of the individual viruses. His lab continues to work with Tm Bioscience to assess performance characteristics of the test using clinical specimens.

Tm Bioscience plans to launch successive versions of its Upper Respiratory Infectious Disease Panel over time. The first version of the panel, which detects and differentiates among various strains of Respiratory Syncitial Virus (RSV), SARS Corona Virus, Parainfluenza and Influenza Virus A/B including H5N1 (Avian Flu), is currently being tested.

Subsequent versions of the test will be expanded to include additional viruses and may identify specific mutant variants of the H5N1 virus that are capable of human-to-human transmission.



Heart failure blood test

A large-scale international study has demonstrated the usefulness of a blood test to confirm or exclude the diagnosis of acute heart failure in emergency room patients and shows that the test also can identify patients at a higher risk for death. The report from investigators in the United States, the Netherlands, Spain and New Zealand also clarifies the importance of age-specific levels of a protein called NTproBNP that definitively diagnose heart failure.

The report appears in the European Heart Journal. “In an analysis of patients from several parts of the world, we showed that this test is greatly valuable in the diagnosis and prognosis of patients with both systolic and diastolic heart failure,” says James Januzzi Jr, MD, of the MGH Cardiology Division, the paper's co-lead author.

“It's a single blood test that can provide multiple pieces of important information.” Congestive heart failure, which occurs when an impaired heart muscle cannot pump blood efficiently, is a growing health problem and major cause of cardiac death. The diagnosis of heart failure may be challenging because its symptoms can overlap those of other conditions. Earlier last year Dr Januzzi and colleagues from the MGH published the PRIDE study, the first prospective American trial measuring NT-proBNP in patients coming to a hospital emergency department with shortness of breath.

Other research groups, including collaborators in the current study, have conducted single-site investigations supporting the usefulness of NT-proBNP for confirming a diagnosis of heart failure. The International Collaborative of NT-proBNP (ICON) Study brought together data from the PRIDE study and similar information from the Christchurch Cardioendocrine Research Group in New Zealand and the Hospital de la Santa Creu i Sant Pau in Barcelona, Spain, with previously unpublished information gathered by researchers from the University Hospital of Maastricht, The Netherlands, led by co-lead author Roland van Kimmenade, MD.

Their analysis consisted of information from 1,256 patients, of which 720 had acute heart failure. As in the earlier studies, NT-proBNP levels were significantly higher in patients found to have heart failure and highest in those with the most severe symptoms. The larger scale of the study permitted more indepth analysis of data, allowing the establishment of age-specific NT-proBNP levels defining a clear diagnosis of heart failure. The measurement below which heart failure could be ruled out was the same for all age groups.

Analysis of the prospective value of NT-proBNP testing showed that patients who died within a little more than two months after symptom onset had significantly higher blood levels of the protein. In fact, NTproBNP measurement was the single strongest predictor of death within that time period, and those with the most significantly elevated levels had a fivefold increase in the risk of death.



Cancer Genome Atlas

The US-based National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the US National Institutes of Health (NIH), has launched a comprehensive effort to accelerate the understanding of the molecular basis of cancer through the application of genome analysis technologies, especially large-scale genome sequencing.

The overall effort, called The Cancer Genome Atlas (TCGA), will begin with a pilot project to determine the feasibility of a full-scale effort to systematically explore the universe of genomic changes involved in all types of human cancer. “Now is the time to move forward with this pioneering initiative. Thanks to the tools and technologies developed by the Human Genome Project and recent advances in using genetic information to improve cancer diagnosis and treatment, it is now possible to envision a systematic effort to map the changes in the human genetic blueprint associated with all known forms of cancer,” said NIH director Elias A Zerhouni, MD.

“This atlas of genomic changes will provide new insights into the biological basis of cancer, which in turn will lead to new tests to detect cancer in its early, most treatable stages; new therapies to target cancer at its most vulnerable points; and, ultimately, new strategies to prevent cancer.” NCI and NHGRI have each committed US$50 million over three years to the TCGA Pilot Project.

The project will develop and test the complex science and technology framework needed to systematically identify and characterise the genetic mutations and other genomic changes associated with cancer. The pilot will involve a few types of cancer that will be chosen for their value in helping to determine the feasibility of a possible larger-scale project. The process for determining the types of cancers to be studied is currently underway. Cancer is now understood to include more than 200 different diseases. In all forms of cancer, genomic changes – often specific to a particular type or stage of cancer – cause disruptions within cellular pathways that result in uncontrolled cell growth.

TCGA will delve more deeply into the genetic origins leading to this complex set of diseases, and, in doing so, will create new discoveries and tools that will provide the basis for a new generation of cancer therapies, diagnostics, and preventive strategies. Genetic mutations linked to breast cancer, colon cancer, melanoma, and other cancers already have led to diagnostic tests that can point to the most effective intervention.

Recent discoveries in cancer genomics have helped to identify several treatments that work by targeting cancer cells with a specific genetic change, such as Gleevec, a drug for chronic myeloid leukemia and gastrointestinal stromal tumours, and Herceptin, a drug for one form of breast cancer. These successful developments support further examination of the molecular origins of cancer to more quickly develop new tools to diagnose, treat, and prevent cancer.

The data from TCGA centers will be deposited in public databases supported by NCI's cancer Biomedical Informatics Grid (caBIG) and the National Library of Medicine's National Center for Biotechnology Information. As in the Human Genome Project, TCGA data will be made available to the worldwide research community. For more information about The Cancer Genome Atlas, visit: http://cancergenome.nih.gov



Fear factor

Knocking out a gene in the brain's fear hub creates mice unperturbed by situations that would normally trigger instinctive or learned fear responses, researchers funded in part by the US National Institutes of Health have discovered. The findings may lead to improved treatments for anxiety disorders they suggest.

The scientific team, led by US-based National Institute of Mental Health (NIMH) grantee and Nobel Laureate Dr Eric Kandel, Columbia University, Dr Vadim Bolshakov, Harvard University, a grantee of the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Drug Abuse (NIDA), and Dr Gleb Shumyatsky, Rutgers University, report on their study in the November 18, 2005 issue of Cell. Fear memories are so essential for survival that they are easily formed and rarely lost. The workings of fear circuitry, centered in the amygdala, an almondshaped structure deep in the brain, are well understood.

But relatively little is known about fear's molecular basis, note the researchers. The gene in the current study codes for stathmin, a protein that appears to be critical for the amygdala to rearrange connections and form fear memories. Stathmin normally controls this process by regulating the supply of microtubules, building materials that amygdala cells use to make structural adaptations that encode the memories. Runaway production of these building materials stymied construction of fear memories in a mouse strain molecularly engineered to lack stathmin, the researchers found.

They first showed that circuitry on the side of the amygdala known to be critical for fear learning is rich in stathmin. They then demonstrated that a cellular process critical for memory formation, long-term potentiation, is impaired there in stathmin knockout mice, due to the excess production of microtubules. Compared to control animals, the stathmin knockout mice showed less anxiety (freezing) when they heard a tone that had previously been associated with a shock, indicating less learned fear. The knockout mice also were more prone to explore novel open space and maze environments, a reflection of less innate fear.

“Stathmin knockout mice can be used as a model of anxiety states of mental disorders with innate and learned fear components,” propose the researchers. "As a corollary, these animal models could be used to develop new anti-anxiety agents.” This and related studies with other knockout mouse models suggest that subclasses of anxiety disorders will ultimately emerge, “each of which is likely to have a unique molecular signature and require distinctive pharmacological approaches,” they add. “Whether stathmin is similarly expressed and pivotal for anxiety in the human amygdala remains to be confirmed,” noted NIMH director Dr Thomas Insel. “Yet, this surprising discovery in the mouse hints at the potential for new treatment strategies likely still hidden in the vast uncharted territory of brain genetics.”



Meditation

The regular practice of meditation appears to produce structural changes in areas of the brain associated with attention and sensory processing. An imaging study led by the US-based Massachusetts General Hospital (MGH) researchers showed that particular areas of the cerebral cortex, the outer layer of the brain, were thicker in participants who were experienced practitioners of a type of meditation commonly practiced in the US and other Western countries. The article appears in the 15 November, 2005 issue of NeuroReport.

“Our results suggest that meditation can produce experience-based structural alterations in the brain,” says Sara Lazar, PhD, of the MGH Psychiatric Neuroimaging Research Program, the study's lead author. “We also found evidence that mediation may slow down the aging-related atrophy of certain areas of the brain.” Studies have shown that meditation can produce alterations in brain activity, and meditation practitioners have described changes in mental function that last long after actual meditation ceases, implying long-term effects. However, those studies usually examined Buddhist monks who practiced mediation as a central focus of their lives.

To investigate whether meditation as typically practiced in the US could change the brain's structure, the current study enrolled 20 practitioners of Buddhist Insight meditation – which focuses on “mindfulness,” a specific, nonjudgmental awareness of sensations, feelings and state of mind. They averaged nine years of meditation experience and practiced about six hours per week. For comparison, 15 people with no experience of meditation or yoga were enrolled as controls.

Using standard MRI to produce detailed images of the structure of participants' brains, the researchers found that regions involved in the mental activities that characterise Insight meditation were thicker in the meditators than in the controls, the first evidence that alterations in brain structure may be associated with meditation.

They also found that, in an area associated with the integration of emotional and cognitive processes, differences in cortical thickness were more pronounced in older participants, suggesting that meditation could reduce the thinning of the cortex that typically occurs with aging. “The area where we see these differences is involved in both the modulation of functions like heart rate and breathing and also the integration of emotion with thought and reward-based decision making – a central switchboard of the brain,” says Lazar. An instructor in Psychology at Harvard Medical School, she also stresses that the results of such a small study need to be validated by larger, longer-term studies.

                                  
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